Replacement of connexin 40 by connexin 45 causes ectopic localization of renin-producing cells in the kidney but maintains in vivo control of renin gene expression

Abstract

Deletion of connexin 40 (Cx40) leads to ectopic hyperplasia of renin-producing cells in the kidney, which is associated with dysregulated hyperreninemia and hypertension. The aim of this study was to determine whether Cx45 is able to substitute the function of Cx40 with regard to the localization of renin-producing cells. For this purpose, we have studied the distribution of renin-expressing cells under both normal conditions and during a stimulatory challenge of the renin system by inducing salt deprivation in mice, achieved by replacing the coding sequence of the Cx40 gene with that of Cx45 (Cx40ki45). In both wild-type (WT) mice and Cx40ki45 mice under normal conditions, renin-expressing cells were located at the juxtaglomerular position, whereas in Cx40-deficient mice they were located in the periglomerular interstitium. Upon challenge of the renin system, renin mRNA and the number of renin-expressing cells increased in WT mice in the media layer of afferent arterioles, while neither parameter changed significantly in Cx40-deficient mice. In Cx40ki45 mice, challenge of the renin system markedly increased both renin mRNA and the number of renin-expressing cells. However, the newly recruited renin-expressing cells were localized mainly outside the afferent vessels in the periglomerular interstitium. We found no evidence of cell divisions in renin-expressing cells in any of the genotypes investigated in this study, suggesting that the ectopically localized, renin-expressing cells in Cx40ki45 mice were already preexisting but were not renin-expressing under normal conditions. In summary, we infer from our findings that the function of Cx40 for the localization of potential renin-producing cells cannot be substituted by that of Cx45, although the regulability of renin gene expression can.